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1.
ACS Chem Biol ; 18(9): 1993-2002, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37622522

RESUMO

Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Qmeth), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Qmeth formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Qmeth-cysteine and Qmeth-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Indolquinonas , Metanfetamina , Humanos , Animais , Camundongos , Ratos , Tacrina/toxicidade , Biotransformação
2.
Drug Chem Toxicol ; 44(2): 207-214, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31257938

RESUMO

The search for tacrine derivatives, as potential Alzheimer´s disease treatment, is still being at the forefront of scientific efforts. 7-MEOTA was found to be a potent, centrally active acetylcholinesterase inhibitor free of the serious side effects observed for tacrine. Unfortunately, a relevant argumentation about pharmacokinetics and potential toxicity is incomplete; information about tacrine derivatives absorption and especially CNS penetration are still rare as well as detailed toxicological profile in vivo. Although the structural changes between these compounds are not so distinctive, differences in plasma profile and CNS targeting were found. The maximum plasma concentration were attained at 18th min (tacrine; 38.20 ± 3.91 ng/ml and 7-MEOTA; 88.22 ± 15.19 ng/ml) after i.m. application in rats. Although the brain profiles seem to be similar; tacrine achieved 19.34 ± 0.71 ng/ml in 27 min and 7-MEOTA 15.80 ± 1.13 ng/ml in 22 min; the tacrine Kp (AUCbrain/AUCplasma) fit 1.20 and was significantly higher than 7-MEOTA Kp 0.10. Administration of tacrine and 7-MEOTA showed only mild elevation of some biochemical markers following single p.o. application in 24 hours and 7 days. Also histopathology revealed only mild-to-moderate changes following repeated p.o. administration for 14 days. It seems that small change in tacrine molecule leads to lower ability to penetrate through the biological barriers. The explanation that lower p.o. acute toxicity of 7-MEOTA depends only on differences in metabolic pathways may be now revised to newly described differences in pharmacokinetic and toxicological profiles.


Assuntos
Encéfalo/metabolismo , Inibidores da Colinesterase/administração & dosagem , Tacrina/análogos & derivados , Animais , Área Sob a Curva , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Masculino , Ratos , Ratos Wistar , Tacrina/administração & dosagem , Tacrina/farmacocinética , Tacrina/toxicidade , Fatores de Tempo , Distribuição Tecidual
3.
Neuropharmacology ; 162: 107829, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31666199

RESUMO

Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons and treated with the dopamine precursor, 3,4-dihydroxy-l-phenylalanine (L-DOPA). Prolonged L-DOPA treatment is however associated with waning efficacy and the induction of L-DOPA induced dyskinesia (LID). GPR88 is an orphan G-protein Coupled Receptor (GPCR) expressed in dopaminoceptive striatal medium spiny neurons (MSNs) and their afferent corticostriatal glutamatergic neurons. Here, we studied the role of GPR88 in experimental parkinsonism and LID. Chronic L-DOPA administration to male GPR88 KO mice, subjected to unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, resulted in more rotations than in their WT counterparts. Conversely, GPR88 KO mice had a lower abnormal involuntary movements (AIMs) score. These behavioral responses were accompanied by altered transcription of L-DOPA upregulated genes in lesioned GPR88 KO compared to WT striata. In accordance with a role for serotonin neurons in LID development, WT but not GPR88 KO striata exhibited 5-hydroxytryptamine displacement upon repeated L-DOPA treatment. Intact male GPR88 KO mice showed diminished tacrine-induced PD-like tremor and spontaneous hyperlocomotion. Dopamine and its metabolites were not increased in male GPR88 KO mice, but biosensor recordings revealed increased spontaneous/basal and evoked glutamate release in striata of male GPR88 KO mice. In conclusion, genetic deletion of GPR88 promotes l-DOPA-induced rotation and spontaneous locomotion yet suppresses the induction of LIDs and also reduces tremor. These data provide behavioral, neurochemical and molecular support that GPR88 antagonism may favour motor relief in PD patients without aggravating the induction of motor side effects.


Assuntos
Antiparkinsonianos/farmacologia , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/genética , Levodopa/farmacologia , Locomoção/efeitos dos fármacos , Movimento/efeitos dos fármacos , Transtornos Parkinsonianos/genética , Receptores Acoplados a Proteínas G/genética , Adrenérgicos/toxicidade , Animais , Inibidores da Colinesterase/toxicidade , Corpo Estriado/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/fisiopatologia , Neurônios GABAérgicos , Ácido Glutâmico/metabolismo , Locomoção/genética , Masculino , Feixe Prosencefálico Mediano , Camundongos , Camundongos Knockout , Plasticidade Neuronal/genética , Oxidopamina/toxicidade , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Serotonina/metabolismo , Tacrina/toxicidade , Tremor
4.
Eur J Pharmacol ; 833: 364-369, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29883670

RESUMO

The present study examines the effect of three adenosine receptor antagonists on tremulous jaw movements (TJMs), an animal model of tremor. Forty-five rats were pre-treated with one adenosine antagonist: caffeine (0.0, 5.0, or 10.0 mg/kg; non-selective adenosine receptor antagonist), 8-cyclopentyltheophylline (CPT; 0.0, 5.0, or 10.0 mg/kg; selective adenosine A1 receptor antagonist), or SCH 58261 (0.0 or 8.0 mg/kg; selective adenosine A2A receptor antagonist) followed by TJM induction with tacrine (0.0, 0.75, or 2.5 mg/kg; acetylcholinesterase inhibitor). CPT and SCH 58261 both significantly reduced TJMs while caffeine did not. Unexpectedly, both SCH 58261 and CPT reduced TJMs even in the absence of tacrine. Also, CPT showed a robust reduction of TJMs, achieved at both (5.0 mg/kg) and (10.0 mg/kg) doses and regardless of tacrine dose. In conclusion, this study shows adenosine receptor antagonism to generally suppress low-dose tacrine-induced TJMs. In concert with two prior studies, these results are suggestive of behavioral evidence for a biphasic effect of adenosine A2A receptor antagonists (caffeine and SCH 58261) that is modulated by tacrine, and a model of this effect is proposed.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Adenosina/antagonistas & inibidores , Doença de Parkinson/tratamento farmacológico , Tremor/tratamento farmacológico , Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Cafeína/farmacologia , Cafeína/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Arcada Osseodentária , Masculino , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tacrina/toxicidade , Teofilina/análogos & derivados , Teofilina/farmacologia , Teofilina/uso terapêutico , Tremor/induzido quimicamente , Triazóis/farmacologia , Triazóis/uso terapêutico
5.
Eur J Med Chem ; 144: 128-136, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29268129

RESUMO

A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced ß-amyloid (Aß) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Tacrina/análogos & derivados , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Compostos de Bifenilo/toxicidade , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inibidores da Colinesterase/toxicidade , Colinesterases/metabolismo , Desenho de Fármacos , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Células PC12 , Ratos , Tacrina/toxicidade
6.
Curr Alzheimer Res ; 15(6): 552-560, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29231138

RESUMO

BACKGROUND: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. METHODS: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. RESULTS: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. CONCLUSION: Observed effects predetermined 6-chlorotacrine as a potent parent compound for the synthesis of novel multifactorial drugs intended to the treatment of Alzheimer's disease. Even though 6- chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose the exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.


Assuntos
Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Tacrina/análogos & derivados , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Nootrópicos/química , Nootrópicos/farmacologia , Nootrópicos/toxicidade , Ratos Wistar , Tacrina/química , Tacrina/farmacologia , Tacrina/toxicidade
7.
Hepatology ; 67(1): 282-295, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28646502

RESUMO

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher ß-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral ß-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. CONCLUSION: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295).


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Tacrina/toxicidade , Animais , Biópsia por Agulha , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Testes de Função Hepática , Masculino , Distribuição Aleatória , Ratos , Ratos Endogâmicos , Valores de Referência , Índice de Gravidade de Doença , Tacrina/farmacocinética , Tacrina/farmacologia
8.
J Psychiatry Neurosci ; 42(1): 59-69, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27636528

RESUMO

BACKGROUND: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-ß aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data. METHODS: We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells. RESULTS: In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine. LIMITATIONS: The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration. CONCLUSION: ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Indóis/administração & dosagem , Aprendizagem/efeitos dos fármacos , Nootrópicos/administração & dosagem , Piperidinas/administração & dosagem , Doença de Alzheimer/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Donepezila , Gliose/tratamento farmacológico , Gliose/patologia , Células Hep G2 , Hipocampo/metabolismo , Humanos , Indanos/toxicidade , Indóis/química , Indóis/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Nootrópicos/química , Nootrópicos/toxicidade , Piperidinas/química , Piperidinas/toxicidade , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Estudo de Prova de Conceito , Reconhecimento Psicológico/efeitos dos fármacos , Escopolamina , Tacrina/toxicidade
9.
ChemMedChem ; 11(12): 1264-9, 2016 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-26427608

RESUMO

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 µm), butyrylcholinesterase (BChE IC50 : 2.4 µm) and MAO A (IC50 : 0.49 µm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 µm). Although its cytotoxic (IC50 : 5.5±0.4 µm) and hepatotoxic (IC50 : 1.22±0.11 µm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 µm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Indóis/síntese química , Inibidores da Monoaminoxidase/uso terapêutico , Quinolinas/síntese química , Tacrina/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Células Hep G2 , Humanos , Indóis/química , Indóis/metabolismo , Indóis/uso terapêutico , Indóis/toxicidade , Concentração Inibidora 50 , Ligantes , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/toxicidade , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/uso terapêutico , Quinolinas/toxicidade , Relação Estrutura-Atividade , Tacrina/metabolismo , Tacrina/uso terapêutico , Tacrina/toxicidade
10.
J Med Chem ; 58(22): 8985-9003, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26503905

RESUMO

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Cromanos/química , Cromanos/farmacologia , Tacrina/química , Tacrina/farmacologia , Acetilcolinesterase/química , Animais , Antioxidantes/toxicidade , Barreira Hematoencefálica , Catálise , Inibidores da Colinesterase/toxicidade , Cromanos/toxicidade , Desenho de Fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Hepatócitos/efeitos dos fármacos , Humanos , Injeções Intramusculares , Cinética , Ligantes , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Wistar , Tacrina/toxicidade
11.
Indian J Exp Biol ; 53(5): 292-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26040026

RESUMO

The effect of ethanolic extract of Coriandrum sativum L. seeds (100, 200 mg/kg) was studied on tacrine induced orofacial dyskinesia. Tacrine (2.5 mg/kg, i.p.) treated animals were observed for vacuous chewing movements (VCM), tongue protrusions (TP) and orofacial bursts (OB) for 1 h followed by observations for locomotor changes and cognitive dysfunction. Sub-chronic administration of Coriandrum sativum L. seed extract (E-CS) (100, 200 mg/kg, p.o., for 15 days significantly (P < 0.05) decreased the tacrine induced VCM, TP and OB; and also significantly (P < 0.05), increased locomotion and cognition compared to the tacrine treated group. Biochemical analysis revealed that tacrine administration significantly (P < 0.05) decreased the levels of superoxide dismutase (SOD), Catalase (CAT), glutathione reductase (GSH) levels and also significantly (P < 0.05) increased lipid peroxidation (LPO) as an index of oxidative stress, whereas subchronic administration of E-CS significantly (P < 0.05) improved the antioxidant enzyme (i.e. SOD, CAT, and GSH) levels and also significantly (P < 0.05) decreased lipid peroxidation (LPO). The results have demonstrated the protective role of ethanolic extract of Coriandrum sativum. L against tacrine induced orofacial dyskinesia.


Assuntos
Peroxidação de Lipídeos/efeitos dos fármacos , Transtornos dos Movimentos/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Coriandrum/química , Transtornos dos Movimentos/patologia , Extratos Vegetais/química , Ratos , Ratos Wistar , Tacrina/toxicidade
12.
Pharmacol Res ; 97: 40-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25890194

RESUMO

Previous work by our laboratory has shown that tacrine can produce long-lasting reductions in cocaine-reinforced behavior, when administered to rats as daily intravenous infusions over four days. Tacrine causes dose-related liver toxicity in different species, and its manufacture for human use was recently discontinued. This study was conducted to further characterize its actions on cocaine reward. Cocaine-experienced animals that had no contact with drug over one week resumed self-administration at levels similar to their initial baseline. When tacrine was administered over four days which were preceded and followed by washout periods to allow elimination of cocaine and tacrine respectively, subsequent cocaine self-administration was attenuated by more than one-half. Tacrine administered at 10 mg/kg-day as a chronic infusion by osmotic pump did not modify cocaine-induced increases in locomotor activity or conditioned-place preference. In rats that exhibited persistent attenuation of cocaine-self-administration after receiving tacrine, cocaine-induced reinstatement was also attenuated. No changes in plasma measures of renal or hepatic function were observed in rats receiving tacrine. In conclusion, pretreatment with tacrine can decrease cocaine-motivated behavior measured by self-administration or reinstatement, but not conditioned-place preference. Reductions in cocaine self-administration following pretreatment with tacrine do not require direct interaction with cocaine and are not secondary to either liver or kidney toxicity.


Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Nootrópicos/farmacologia , Recompensa , Tacrina/farmacologia , Animais , Agonistas Colinérgicos/farmacologia , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/psicologia , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Alimentos , Bombas de Infusão , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Nootrópicos/toxicidade , Ratos , Ratos Wistar , Autoadministração , Tacrina/toxicidade
13.
J Pharm Pharmacol ; 67(8): 1170-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25773602

RESUMO

OBJECTIVES: Fucosterol is the primary sterol found in brown algae. Recently, considerable interest has been generated regarding fucosterol due to its potential antioxidant, anti-inflammatory and antidiabetic effects. The aim of this study was to investigate the protective effects of fucosterol on tert-butyl hydroperoxide (t-BHP)- and tacrine-induced oxidative stress in HepG2 cells. METHODS: Fucosterol by itself exhibited no cytotoxicity at concentrations below 100 µm by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The increased intracellular reactive oxygen species (ROS) and decreased glutathione levels observed in t-BHP- and tacrine-treated HepG2 cells were ameliorated by fucosterol pretreatment, indicating that the protective effects of fucosterol are mediated by the induction of cellular defence mechanisms against oxidative stress. Moreover, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in tacrine-treated mice were significantly reduced after oral administration of fucosterol. KEY FINDINGS: The hepatoprotective effects of fucosterol may occur via an increase in the hepatic level of glutathione and a decrease in ROS production, thereby preventing hepatic damage and the resultant increases in ALT and AST activity. CONCLUSION: These results suggest that fucosterol may be an effective hepatoprotective agent that could be useful for preventive therapies against oxidative stress-related hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Phaeophyceae , Substâncias Protetoras/farmacologia , Estigmasterol/análogos & derivados , Animais , Sobrevivência Celular , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Células Hep G2 , Humanos , Masculino , Camundongos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Estigmasterol/farmacologia , Tacrina/toxicidade , terc-Butil Hidroperóxido/toxicidade
14.
Biol Pharm Bull ; 38(2): 184-92, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25747977

RESUMO

Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H2O2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3ß (GSK3ß) and prevented decreases in GSK3ß phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inibidores da Colinesterase/toxicidade , Flavanonas/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Substâncias Protetoras/uso terapêutico , Tacrina/toxicidade , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Flavanonas/farmacologia , Glutationa/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Peróxido de Hidrogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
15.
Mini Rev Med Chem ; 15(8): 648-58, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25694076

RESUMO

This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Tacrina/química , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/toxicidade , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/toxicidade , Colinesterases/metabolismo , Descoberta de Drogas , Células Hep G2 , Humanos , Modelos Moleculares , Nootrópicos/química , Nootrópicos/farmacologia , Nootrópicos/toxicidade , Sesquiterpenos/toxicidade , Tacrina/toxicidade
16.
Int J Pharm ; 477(1-2): 442-53, 2014 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-25445524

RESUMO

Tacrine (THA), as the first approved acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD), has been extensively investigated in last seven decades. After dimerization of THA via a 7-carbon alkyl spacer, bis(7)-tacrine (B7T) showed much potent anti-AChE activity than THA. We here report synthesis, biological evaluation and biopharmaceutical characterization of six THA dimers referable to B7T. According to IC50 values, the in vitro anti-AChE activities of THA dimers were up to 300-fold more potent and 200-fold more selective than that of THA. In addition, the anti-AChE activities of THA dimers were found to be associated with the type and length of the linkage. All studied THA dimers showed much lower cytotoxicity than B7T, but like B7T, they demonstrated much lower absorptive permeabilities than that of THA on Caco-2 monolayer model. In addition, all THA dimers demonstrated significant efflux transport (efflux ratio >4), indicating that the limited permeability could be associated with the efflux transport during absorption process. Moreover, the dimer with higher Log P value was accompanied with higher permeability but lower aqueous solubility. A balanced consideration of activity, solubility, cytotoxicity and permeability should be conducted in selection of the potential candidates for further in vivo investigation.


Assuntos
Biofarmácia/métodos , Inibidores da Colinesterase/síntese química , Tacrina/análogos & derivados , Transporte Biológico , Células CACO-2 , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Cromatografia Líquida de Alta Pressão , Dimerização , Humanos , Estrutura Molecular , Solubilidade , Tacrina/síntese química , Tacrina/química , Tacrina/farmacocinética , Tacrina/toxicidade , Espectrometria de Massas em Tandem
17.
Toxicol In Vitro ; 28(4): 667-74, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24560791

RESUMO

Tacrine (THA) is a competitive inhibitor of cholinesterase. Administration of THA for the treatment of Alzheimer's disease results in a reversible hepatotoxicity in 30-50% of patients, as indicated by elevated alanine aminotransferase levels. However, the intracellular mechanisms have not yet been elucidated. In our previous study, we found that THA induced cytotoxicity and mitochondria dysfunction by ROS generation and 8-OHdG formation in mitochondrial DNA in HepG2 cells. In this study, the mechanism underlying was further investigated. Our results demonstrated that THA induced dose-dependent apoptosis with cytochrome c release and activation of caspase-3. THA-induced apoptosis was inhibited by treating cells with a ROS inhibitor, YCG063. In addition, we observed that THA led to an early lysosomal membrane permeabilization and release of cathepsin B. Pretreatment with CA-074Me, a specific cathepsin B inhibitor resulted in a significant but not complete decrease in tacrine-induced apoptosis. These data suggest that tacrine-induced cell apoptosis involves both mitochondrial damage and lysosomal membrane destabilization, and ROS is the critical factor that integrates tacrine-induced mitochondrial and lysosomal death pathways.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Tacrina/toxicidade , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Sobrevivência Celular , Citocromos c/metabolismo , Dipeptídeos/administração & dosagem , Dipeptídeos/farmacologia , Células Hep G2 , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/farmacologia , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Nitroimidazóis/administração & dosagem , Nitroimidazóis/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tacrina/administração & dosagem
18.
Eur J Med Chem ; 74: 491-501, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24502897

RESUMO

The pharmacological analysis of racemic chromenotacrines (CT) 1-7, bearing the 11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol ring skeleton, in a series of experiments targeted to explore their potential use for the treatment of Alzheimer's disease (AD), is reported. The toxicological evaluation showed that among all these chromenotacrines, CT6 is much less hepatotoxic than tacrine in a range of concentrations from 1 to 300 µM, measured as cell viability in HepG2 cells. Moreover, CT6 did not significantly increase lactate dehydrogenase, aspartate transaminase, and alanine transaminase release in HepG2 cells. Besides, CT6 treatment exerts a high protective effect against the lipid peroxidation induced after H2O2-treated SH-SY5Y cells, in a concentration-dependent manner. CT6 showed an excellent antioxidant profile in the AAPH test, and protects against the decrease in cell viability induced by respiratory chain inhibitors (Oligomicyn A/Rotenone) and NO donors in neuronal cultures. This effect could be due to a mixed antiapoptotic and antinecrotic neuroprotective effect at low and intermediate CT6 concentrations, respectively. CT1-7 are potent and selective inhibitors of EeAChE in the submicromolar range. CT3 [IC50 (EeAChE) = 0.007 ± 0.003 µM], and CT6 [IC50 (EeAChE) = 0.041 ± 0.001 µM] are the most potent AChE inhibitors. Kinetic studies on the non-toxic chromenotacrine CT6 showed that this compound behaves as a non-competitive inhibitor (Ki = 0.047 ± 0.003 µM), indicating that CT6 binds at the peripheral anionic site, a fact confirmed by molecular modeling analysis. In silico ADMET analysis showed also that CT6 should have a moderate BBB permeability. Consequently, non-toxic chromenotacrine CT6 can be considered as an attractive multipotent molecule for the potential treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Antioxidantes/uso terapêutico , Tacrina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/química , Antioxidantes/toxicidade , Linhagem Celular Tumoral , Inibidores da Colinesterase/química , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/toxicidade , Humanos , Modelos Moleculares , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/toxicidade , Estereoisomerismo , Tacrina/química , Tacrina/uso terapêutico , Tacrina/toxicidade
19.
Exp Neurol ; 253: 180-91, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24412491

RESUMO

Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor heteromers in co-transfected cells as well as in rat striatum. These data suggest that treatment with a combination of drugs or a single compound selectively acting on A2A-CB1-D2 heteromers may represent an alternative therapeutic treatment of PD. We investigated the expression of A2A-CB1-D2 receptor heteromers in the striatum of both naïve and hemiparkinsonian rats (HPD-rats) bearing a unilateral 6-hydroxydopamine (6-OHDA) lesion, and assessed how receptor heteromer expression and biochemical properties were affected by L-DOPA treatment. Radioligand binding data showed that A2A-CB1-D2 receptor heteromers are present in the striatum of both naïve and HPD-rats. However, behavioral results indicated that the combined administration of A2A (MSX-3 or SCH58261) and CB1 (rimonabant) receptor antagonists, in the presence of L-DOPA does not produce a response different from administration of the A2A receptor antagonist alone. These behavioral results prompted identification of heteromers in L-DOPA-treated animals. Interestingly, the radioligand binding results in samples from lesioned animals suggest that the heteromer is lost following acute or chronic treatment with L-DOPA.


Assuntos
Antiparkinsonianos/farmacologia , Corpo Estriado/metabolismo , Lateralidade Funcional/efeitos dos fármacos , Levodopa/farmacologia , Transtornos Parkinsonianos/patologia , Receptor Cross-Talk/fisiologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Inibidores da Colinesterase/toxicidade , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Lateralidade Funcional/fisiologia , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk/efeitos dos fármacos , Rimonabanto , Tacrina/toxicidade , Fatores de Tempo , Tremor/induzido quimicamente
20.
Org Biomol Chem ; 12(5): 801-14, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24310227

RESUMO

A series of tacrine-rhein hybrid compounds have been designed and synthesized as novel multifunctional potent ChE inhibitors. Most of the compounds inhibited ChEs in the nanomolar range in vitro effectively. Compound 10b was one of the most potent inhibitors and was 5-fold more active than tacrine toward AChE, and it also showed a moderate BuChE inhibition with an IC50 value of 200 nM. Kinetic and molecular modeling studies of 10b also indicated that it was a mixed-type inhibitor binding simultaneously to the active and peripheral sites of AChE. In inhibition of the AChE-induced Aß aggregation assay, compound 10b (70.2% at 100 µM) showed the greatest inhibitory activity. In addition, 10b showed metal-chelating property and low hepatotoxicity. These results suggested that 10b might be an excellent multifunctional agent for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antraquinonas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Tacrina/síntese química , Tacrina/farmacologia , Peptídeos beta-Amiloides/química , Animais , Técnicas de Química Sintética , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Cinética , Fígado/efeitos dos fármacos , Metais/química , Camundongos , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Tacrina/química , Tacrina/toxicidade
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